TOKYO and BOTHELL, Wash., March
26, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE:
4503, President and CEO: Kenji
Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN)
today announced that a marketing authorization application (MAA)
for enfortumab vedotin was accepted by the European Medicines
Agency (EMA). The MAA requests review of enfortumab vedotin for the
treatment of adult patients with locally advanced or metastatic
urothelial cancer who have received a programmed death receptor-1
(PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and who have
received a platinum-containing chemotherapy in the
neoadjuvant/adjuvant, locally advanced or metastatic setting. If
approved, enfortumab vedotin would be the first antibody-drug
conjugate (ADC) available in the European Union for people living
with urothelial cancer.
Enfortumab vedotin will be reviewed under accelerated
assessment, which means the EMA's Committee for Medicinal Products
for Human Use (CHMP) can reduce the timeframe for evaluation.
The MAA is based on the global phase 3 EV-301 trial, which
evaluated enfortumab vedotin versus chemotherapy in adult patients
with locally advanced or metastatic urothelial cancer who were
previously treated with platinum-based chemotherapy and a PD-1/L1
inhibitor. Results from the trial, which had a primary endpoint of
overall survival for patients treated with PADCEV versus
chemotherapy, were published in the New England Journal of
Medicine.
"In the European Union, it is estimated that 118,000 people are
diagnosed with urothelial cancer each year, and 52,000 die as a
result of the disease," said Andrew
Krivoshik, M.D., Ph.D., Senior Vice President and Oncology
Therapeutic Area Head, Astellas. "People with advanced urothelial
cancer face an urgent need for new treatment options, which is
reflected in the CHMP's decision to grant accelerated assessment.
We will continue to work with the CHMP toward our goal of securing
marketing authorization as soon as possible."
About Urothelial Cancer
Urothelial
cancer is the most common type of bladder cancer (90 percent of
cases), and can also be found in the renal pelvis (where urine
collects inside the kidney), ureter (tube that connects the kidneys
to the bladder) and urethra.1 Globally, approximately
549,000 new cases of bladder cancer and 200,000 deaths are reported
annually.2 In Europe,
it is estimated that 118,000 patients are diagnosed with this form
of cancer and 52,000 deaths are reported annually.3
Locally advanced and metastatic urothelial cancer
is an aggressive disease that is associated with poor survival and
high healthcare costs.4 Five-year relative survival
rates for metastatic disease are estimated to be approximately 7
percent.5
About the EV-301 Trial
The EV-301 trial (NCT03474107)
is a global, multicenter, open-label, randomized phase 3 trial
designed to evaluate enfortumab vedotin versus physician's choice
of chemotherapy (docetaxel, paclitaxel or vinflunine) in
approximately 600 patients with locally advanced or metastatic
urothelial cancer who were previously treated with a PD-1/L1
inhibitor and platinum-based therapies. The primary endpoint is
overall survival and secondary endpoints include progression-free
survival, overall response rate, duration of response and disease
control rate, as well as assessment of safety/tolerability and
quality-of-life parameters.6
About Enfortumab Vedotin
Enfortumab vedotin is an
antibody-drug conjugate (ADC) that is directed against Nectin-4, a
protein located on the surface of cells and highly expressed in
bladder cancer.7,8 Nonclinical data suggest the
anticancer activity of enfortumab vedotin is due to its binding to
Nectin-4 expressing cells followed by the internalization and
release of the anti-tumor agent monomethyl auristatin E (MMAE) into
the cell, which result in the cell not reproducing (cell cycle
arrest) and in programmed cell death (apoptosis).8
PADCEV (enfortumab vedotin-ejfv) U.S. Important Safety
Information
Warnings and Precautions
Skin reactions: Severe cutaneous adverse reactions,
including fatal cases of Stevens-Johnson syndrome (SJS) or toxic
epidermal necrolysis (TEN), occurred in patients treated with
PADCEV. SJS and TEN occurred predominantly during the first
cycle of treatment but may occur later.
Skin reactions occurred in 54% of the 310 patients treated with
PADCEV in clinical trials. Twenty-six percent (26%) of patients had
maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions
occurred in 10% of patients and included symmetrical drug-related
intertriginous and flexural exanthema (SDRIFE), dermatitis bullous,
dermatitis exfoliative, and palmar-plantar erythrodysesthesia.
In one clinical trial, the median time to onset of severe skin
reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who
experienced rash, 65% had complete resolution and 22% had partial
improvement.
Monitor patients closely throughout treatment for skin
reactions. Consider topical corticosteroids and antihistamines as
clinically indicated. Withhold PADCEV and consider referral for
specialized care for severe (Grade 3) skin reactions, suspected
SJS, or TEN. Permanently discontinue PADCEV in patients with
confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin
reactions.
Hyperglycemia occurred in patients treated with
PADCEV, including death and diabetic ketoacidosis, in those with
and without pre-existing diabetes mellitus. The incidence of Grade
3-4 hyperglycemia increased consistently in patients with higher
body mass index and in patients with higher baseline A1C. In
one clinical trial, 8% of patients developed Grade 3-4
hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were
excluded. Closely monitor blood glucose levels in patients with, or
at risk for, diabetes mellitus or hyperglycemia. If blood glucose
is elevated (>250 mg/dL), withhold PADCEV.
Peripheral neuropathy (PN), predominantly sensory,
occurred in 49% of the 310 patients treated with PADCEV in clinical
trials; 2% experienced Grade 3 reactions. In one clinical trial,
peripheral neuropathy occurred in patients treated with PADCEV with
or without preexisting peripheral neuropathy. The median time to
onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy
led to treatment discontinuation in 6% of patients. At the time of
their last evaluation, 19% had complete resolution, and 26% had
partial improvement. Monitor patients for symptoms of new or
worsening peripheral neuropathy and consider dose interruption or
dose reduction of PADCEV when peripheral neuropathy occurs.
Permanently discontinue PADCEV in patients that develop Grade ≥3
peripheral neuropathy.
Ocular disorders occurred in 46% of the 310 patients
treated with PADCEV. The majority of these events involved the
cornea and included keratitis, blurred vision, limbal stem cell
deficiency and other events associated with dry eyes. Dry eye
symptoms occurred in 36% of patients, and blurred vision occurred
in 14% of patients, during treatment with PADCEV. The median time
to onset to symptomatic ocular disorder was 1.9 months (range: 0.3
to 6.2). Monitor patients for ocular disorders. Consider artificial
tears for prophylaxis of dry eyes and ophthalmologic evaluation if
ocular symptoms occur or do not resolve. Consider treatment with
ophthalmic topical steroids, if indicated after an ophthalmic exam.
Consider dose interruption or dose reduction of PADCEV for
symptomatic ocular disorders.
Infusion site extravasation: Skin and soft tissue
reactions secondary to extravasation have been observed after
administration of PADCEV. Of the 310 patients, 1.3% of patients
experienced skin and soft tissue reactions. Reactions may be
delayed. Erythema, swelling, increased temperature, and pain
worsened until 2-7 days after extravasation and resolved within 1-4
weeks of peak. One percent (1%) of patients developed extravasation
reactions with secondary cellulitis, bullae, or exfoliation. Ensure
adequate venous access prior to starting PADCEV and monitor for
possible extravasation during administration. If extravasation
occurs, stop the infusion and monitor for adverse
reactions.
Embryo-fetal toxicity: PADCEV can cause fetal harm
when administered to a pregnant woman. Advise patients of the
potential risk to the fetus. Advise female patients of reproductive
potential to use effective contraception during PADCEV treatment
and for 2 months after the last dose. Advise male patients with
female partners of reproductive potential to use effective
contraception during treatment with PADCEV and for 4 months after
the last dose.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients treated with
PADCEV. The most common serious adverse reactions (≥3%) were
urinary tract infection (6%), cellulitis (5%), febrile neutropenia
(4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea
(3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of
patients, including acute respiratory failure, aspiration
pneumonia, cardiac disorder, and sepsis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of
patients; the most common adverse reaction leading to
discontinuation was peripheral neuropathy (6%). Adverse reactions
leading to dose interruption occurred in 64% of patients; the most
common adverse reactions leading to dose interruption were
peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse
reactions leading to dose reduction occurred in 34% of patients;
the most common adverse reactions leading to dose reduction were
peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (≥20%) were fatigue (56%),
peripheral neuropathy (56%), decreased appetite (52%), rash (52%),
alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry
eye (40%), pruritus (26%) and dry skin (26%). The most common Grade
≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and
fatigue (6%).
Lab Abnormalities
In one clinical trial, Grade 3-4 laboratory abnormalities reported
in ≥5% were: lymphocytes decreased (10%), hemoglobin decreased
(10%), phosphate decreased (10%), lipase increased (9%), sodium
decreased (8%), glucose increased (8%), urate increased (7%),
neutrophils decreased (5%).
Drug Interactions
Effects of other drugs on PADCEV Concomitant use
with a strong CYP3A4 inhibitor may increase free MMAE exposure,
which may increase the incidence or severity of PADCEV toxicities.
Closely monitor patients for signs of toxicity when PADCEV is given
concomitantly with strong CYP3A4 inhibitors.
Specific Populations
Lactation Advise lactating women not to breastfeed
during treatment with PADCEV and for at least 3 weeks after the
last dose.
Hepatic impairment Avoid the use of PADCEV in
patients with moderate or severe hepatic impairment.
For more information, please see the full Prescribing
Information for PADCEV here.
About the Astellas and Seagen Collaboration
Astellas
and Seagen Inc. are co-developing enfortumab vedotin under a 50:50
worldwide development and commercialization collaboration. In
the United States, Astellas and
Seagen co-promote enfortumab vedotin under the brand name
PADCEV® (enfortumab vedotin-ejfv). In the Americas
outside the US, Seagen holds responsibility for commercialization
activities and regulatory filings. Outside of the Americas,
Astellas holds responsibility for commercialization activities and
regulatory filings.
Astellas Cautionary Notes
In this press release,
statements made with respect to current plans, estimates,
strategies and beliefs and other statements that are not historical
facts are forward-looking statements about the future performance
of Astellas. These statements are based on management's current
assumptions and beliefs in light of the information currently
available to it and involve known and unknown risks and
uncertainties. A number of factors could cause actual results to
differ materially from those discussed in the forward-looking
statements. Such factors include, but are not limited to: (i)
changes in general economic conditions and in laws and regulations,
relating to pharmaceutical markets, (ii) currency exchange rate
fluctuations, (iii) delays in new product launches, (iv) the
inability of Astellas to market existing and new products
effectively, (v) the inability of Astellas to continue to
effectively research and develop products accepted by customers in
highly competitive markets, and (vi) infringements of Astellas'
intellectual property rights by third parties.
Information about pharmaceutical products (including products
currently in development), which is included in this press release
is not intended to constitute an advertisement or medical
advice.
Seagen Forward Looking Statements
Certain statements
made in this press release are forward looking, such as those,
among others, relating to the therapeutic potential of enfortumab
vedotin, including its efficacy, safety and therapeutic uses; and
the potential to obtain regulatory approval of enfortumab vedotin
in the European Union. Actual results or developments may differ
materially from those projected or implied in these forward-looking
statements. Factors that may cause such a difference include,
without limitation, the possibility that enfortumab vedotin may not
ultimately be approved in the European Union for the treatment of
adult patients with locally advanced or metastatic urothelial
cancer who have received a programmed death receptor-1 (PD-1) or
programmed death-ligand 1 (PD-L1) inhibitor and who have received a
platinum-containing chemotherapy in the neoadjuvant/adjuvant,
locally advanced or metastatic setting, in a timely manner or
at all; and that setbacks in the development and commercialization
of enfortumab vedotin could occur as a result of the difficulty and
uncertainty of pharmaceutical product development, the risk of
adverse events or safety signals, failure to establish sufficient
efficacy in clinical trials, adverse regulatory actions or other
factors. More information about the risks and uncertainties faced
by Seagen is contained under the caption "Risk Factors" included in
the company's Annual Report on Form 10-K for the year ended
December 31, 2020 filed with the
Securities and Exchange Commission. Seagen disclaims any intention
or obligation to update or revise any forward-looking statements,
whether as a result of new information, future events or otherwise,
except as required by law.
References
1 American Society of
Clinical Oncology. Bladder cancer: introduction. Published
October 2017.
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed March 4, 2021.
2 Cancer today: data visualization tools for
exploring the global cancer burden in 2020.
https://gco.iarc.fr/today/home. Accessed March 4, 2021.
3 Wong MC, Fung FD, Leung C, et al. Scientific
Reports. 2018;8(1):1129.
4 Shah MV, McGovern A, Hepp Z. Targeted Literature
Review of the Burden of Illness in UC (PCN108). Value
Health. 2018;21(3):S32-S33.
5 von der Maase H, Sengelov L, Roberts J, Ricci S,
et al. Long term survival results of a randomized trial comparing
gemcitabine plus cisplatin, with methotrexate, vinblastine,
doxorubicin, plus cisplatin in patients with bladder cancer. J
Clin Oncol. 2005;23(21):4602 8.
6 Powles T, Rosenberg JE, Sonpavde GP, et al.
Enfortumab Vedotin in Previously Treated Advanced Urothelial
Carcinoma. N Engl J Med. 2021; 10.1056/NEJMoa2035807.
7 PADCEV [package insert]. Northbrook, IL: Astellas Pharma Inc.
8 Challita-Eid P, Satpayev D, Yang P, et al.
Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a
Highly Potent Therapeutic Agent in Multiple Preclinical Cancer
Models. Cancer Res 2016;76(10):3003-13.
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SOURCE Astellas Pharma Inc.